Native calcium channels have been classified by their electrophysiological and pharmacological properties as T, L, N, P and Q types (for reviews see McCleskey, E. W. et al. Curr Topics Membr (1991) 39:295-326, and Dunlap, K. et al. Trends Neurosci (1995) 18:89-98). T-type (or low voltage-activated) channels describe a broad class of molecules that transiently activate at negative potentials and are highly sensitive to changes in resting potential. The L, N, P and Q-type channels activate at more positive potentials and display diverse kinetics and voltage-dependent properties. There is some overlap in biophysical properties of the high voltage-activated channels, consequently pharmacological profiles are useful to further distinguish them. L-type channels are sensitive to dihydropyridine agonists and antagonists, N-type channels are blocked by the Conus geographus peptide toxin, .omega.-conotoxin GVIA, and P-type channels are blocked by the peptide .omega.-agatoxin IVA from the venom of the funnel web spider, Agelenopsis aperta. A fourth type of high voltage-activated calcium channel (Q-type) has been described, although whether the Q- and P-type channels are distinct molecular entities is controversial (Sather, W. A. et al. Neuron (1995) 11:291-303; Stea, A. et al. Proc Natl Acad Sci USA (1994) 91:10576-10580). Several types of calcium conductances do not fall neatly into any of the above categories and there is variability of properties even within a category suggesting that additional calcium channels subtypes remain to be classified.
Biochemical analyses show that neuronal high-threshold calcium channels are heterooligomeric complexes consisting of three distinct subunits (.alpha..sub.1, .alpha..sub.2.delta. and .beta.) (reviewed by De Waard, M. et al. Ion Channels (1997) vol. 4, Narahashi, T. ed. Plenum Press, New York). The .alpha..sub.1 subunit is the major pore-forming subunit and contains the voltage sensor and binding sites for calcium channel antagonists. The mainly extracellular .alpha..sub.2 is disulfide-linked to the transmembrane .delta. subunit and both are derived from the same gene and are proteolytically cleaved in vivo. The .beta. subunit is a nonglycosylated, hydrophilic protein with a high affinity of binding to a cytoplasmic region of the .alpha..sub.1 subunit. A fourth subunit, .gamma., is unique to L-type calcium channels expressed in skeletal muscle T-tubules. The isolation and characterization of y-subunit-encoding cDNAs is described in U.S. Pat. No. 5,386,025 which is incorporated herein by reference.
Recently, each of these .alpha..sub.1 subtypes has been cloned and expressed, thus permitting more extensive pharmacological studies. These channels have been designated .alpha..sub.1A -.alpha..sub.1H and .alpha..sub.1S and correlated with the subtypes set forth above. .alpha..sub.1A channels are of the P/Q type; .alpha..sub.1B represents N; .alpha..sub.1C, .alpha..sub.1D and .alpha..sub.1S represent L; .alpha..sub.1E represents a novel type of calcium conductance, and .alpha..sub.1G and .alpha..sub.1H represent two members of the T-type family, reviewed in Stea, A. et al. in Handbook of Receptors and Channels (1994), North, R. A. ed. CRC Press; Perez-Reyes, et al. Nature (1998) 391:896-900. Bech-Hansen et al., Nature Neurosci (1998) 1:264-267.
U.S. Ser. No. 09/107,037 filed Jun. 30, 1998 describes compounds containing benzhydril and 6-membered heterocyclic moieties that show calcium-channel blocking activity, wherein certain members of the disclosed genus are specific to N-type channels. The present invention is directed to compounds structurally related to farnesol whose activity is also N-type specific at low concentrations. Farnesol has previously been shown to be a calcium-channel blocker when used in the micromolar range and to show a preference for inhibition of L-type receptors (Roullet, J.-B., et al., J Biol Chem (1997) 272:32240-32246. This demonstrated activity is exhibited as "open channel" blockage; that is, channels that have been activated by depolarization show inhibited calcium ion flow. This is in contrast to the inactivated channel block which is exhibited, but at nanomolar concentrations, by farnesol and its related compounds and is specific to the N-type channel. Accordingly, these compounds which, like farnesol, promote the inactivation of the N-type channels, preferably at physiological background potential conditions, are useful in treating conditions associated with N-type channel activity, such as stroke and pain.